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Lactobacillus reuteri Maintains a Functional Mucosal Barrier during DSS Treatment Despite Mucus Layer Dysfunction  [PDF]
Johan Dicksved, Olof Schreiber, Ben Willing, Joel Petersson, Sara Rang, Mia Phillipson, Lena Holm, Stefan Roos
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0046399
Abstract: Treatment with the probiotic bacterium Lactobacillus reuteri has been shown to prevent dextran sodium sulfate (DSS)-induced colitis in rats. This is partly due to reduced P-selectin-dependent leukocyte- and platelet-endothelial cell interactions, however, the mechanism behind this protective effect is still unknown. In the present study a combination of culture dependent and molecular based T-RFLP profiling was used to investigate the influence of L. reuteri on the colonic mucosal barrier of DSS treated rats. It was first demonstrated that the two colonic mucus layers of control animals had different bacterial community composition and that fewer bacteria resided in the firmly adherent layer. During DSS induced colitis, the number of bacteria in the inner firmly adherent mucus layer increased and bacterial composition of the two layers no longer differed. In addition, induction of colitis dramatically altered the microbial composition in both firmly and loosely adherent mucus layers. Despite protecting against colitis, treatment with L. reuteri did not improve the integrity of the mucus layer or prevent distortion of the mucus microbiota caused by DSS. However, L. reuteri decreased the bacterial translocation from the intestine to mesenteric lymph nodes during DSS treatment, which might be an important part of the mechanisms by which L. reuteri ameliorates DSS induced colitis.
The Interaction of Large Bowel Microflora with the Colonic Mucus Barrier  [PDF]
Jeffrey P. Pearson,Iain A. Brownlee
International Journal of Inflammation , 2010, DOI: 10.4061/2010/321426
Abstract: The colonic mucus barrier is the first line of defence that the underlying mucosa has against the wide range of potentially damaging agents of microbial, endogenous, and dietary origin that occur within the colonic lumen. The functional component of mucus is the secreted, polymeric glycoprotein mucin. The mucus barrier can either act as an energy source or a support medium for growth to the intestinal microflora. The mucus barrier appears to effectively partition the vast number of microbial cells from the underlying epithelium. The normal functionality and biochemistry of this mucus barrier appears to be lost in diseases of the colorectal mucosa. Germ-free animal studies have highlighted the necessity of the presence of the colonic microflora to drive the maturation of the colonic mucosa and normal mucus production. A number of by-products of the microflora have been suggested to be key luminal drivers of colonic mucus secretion. 1. Background The colonic mucosa is constantly exposed to a wide range of luminal agents that have the potential for either mucosal damage, or mucosal protection. These luminal agents can be of microbial, dietary or endogenous origin. “Normal” colonic transit time varies widely in humans but within physiological boundaries would be between 24 and 48 hours, in comparison to transit through the upper GI tract which occurs within a few hours [1, 2]. Therefore, there is a longer exposure time of the colonic mucosa to luminal agents than to the underlying tissues of other areas of the gut. In addition, due to the role of the colon in the salvage of unabsorbed nutrients and absorption of fluid [3], these luminal agents will be concentrated (particularly in the distal bowel), resulting in further increases of mucosal exposure to these agents. While removal of water from the faecal bulk is likely to reduce the diffusion of agents from the majority of the faecal cross-section, direct contact will still occur between the mucus and the outer surfaces of the colonic luminal contents. The large bowel also plays host to approximately 1013 bacteria and other micro-organisms [4] and is thought to include over 500 bacterial species [5]. As such, changes to the prevalent species within the microfloral population or to microfloral functioning and output within the bowel are likely to be intimately linked with colorectal health and disease [6]. While digestion per se does not tend to occur in the colon, the colonic microflora acts to degrade dietary fibre and/or other dietary factors that escape digestion to produce further agents that could
CD137 Facilitates the Resolution of Acute DSS-Induced Colonic Inflammation in Mice  [PDF]
Julia M. Martínez Gómez, Lieping Chen, Herbert Schwarz, Thomas Karrasch
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0073277
Abstract: Background CD137 and its ligand (CD137L) are potent immunoregulatory molecules that influence activation, proliferation, differentiation and cell death of leukocytes. Expression of CD137 is upregulated in the lamina propria cells of Crohn’s disease patients. Here, the role of CD137 in acute Dextran-Sodium-Sulfate (DSS)-induced colitis in mice was examined. Methods We induced acute large bowel inflammation (colitis) via DSS administration in CD137?/? and wild-type (WT) mice. Colitis severity was evaluated by clinical parameters (weight loss), cytokine secretion in colon segment cultures, and scoring of histological inflammatory parameters. Additionally, populations of lamina propria mononuclear cells (LPMNC) and intraepithelial lymphocytes (IEL) were characterized by flow cytometry. In a subset of mice, resolution of intestinal inflammation was evaluated 3 and 7 days after withdrawal of DSS. Results We found that both CD137?/? and WT mice demonstrated a similar degree of inflammation after 5 days of DSS exposure. However, the resolution of colonic inflammation was impaired in the absence of CD137. This was accompanied by a higher histological score of inflammation, and increased release of the pro-inflammatory mediators granulocyte macrophage colony-stimulating factor (GM-CSF), CXCL1, IL-17 and IFN-γ. Further, there were significantly more neutrophils among the LPMNC of CD137?/? mice, and reduced numbers of macrophages among the IEL. Conclusion We conclude that CD137 plays an essential role in the resolution of acute DSS-induced intestinal inflammation in mice.
Fast Renewal of the Distal Colonic Mucus Layers by the Surface Goblet Cells as Measured by In Vivo Labeling of Mucin Glycoproteins  [PDF]
Malin E. V. Johansson
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0041009
Abstract: The enormous bacterial load and mechanical forces in colon create a special requirement for protection of the epithelium. In the distal colon, this problem is largely solved by separation of the bacteria from the epithelium by a firmly attached inner mucus layer. In addition, an outer mucus layer entraps bacteria to be cleared by distal transport. The mucus layers contain a network of Muc2 mucins as the main structural component. Here, the renewal rate of the inner protective mucus layer was studied as well as the production and secretion of Muc2 mucin in the distal colon. This was performed by intraperitoneal injection of N-azidoacetyl-galactosamine (GalNAz) that was in vivo incorporated during biosynthesis of O-glycosylated glycoproteins. The only gel-forming mucin produced in the colon is the Muc2 mucin and as it carries numerous O-glycans, the granulae of the goblet cells producing Muc2 mucin were intensely stained. The GalNAz-labeled glycoproteins were first observed in the Golgi apparatus of most cells. Goblet cells in the luminal surface epithelium had the fastest biosynthesis of Muc2 and secreted material already three hours after labeling. This secreted GalNAz-labeled Muc2 mucin formed the inner mucus layer. The goblet cells along the crypt epithelium accumulated labeled mucin vesicles for a longer period and secretion of labeled Muc2 mucin was first observed after 6 to 8 h. This study reveals a fast turnover (1 h) of the inner mucus layer in the distal colon mediated by goblet cells of the luminal surface epithelium.
Diversity of Microflora in Colonic Mucus from Severe Ulcerative Colitis Patients Analyzed by Terminal Restriction Fragment Length Polymorphism and Clone Libraries of Bacterial 16S rRNA Gene Sequences  [PDF]
I-Nung Huang, Yuri Sato, Mitsuo Sakamoto, Moriya Ohkuma, Shinobu Ohnuma, Takeshi Naitoh, Chikashi Shibata, Akira Horii, Junko Nishimura, Haruki Kitazawa, Tadao Saito
Advances in Microbiology (AiM) , 2014, DOI: 10.4236/aim.2014.413095
Abstract: Although the gut microflora is thought to be an essential factor in the development of ulcerative colitis (UC), the entire gut microflora occurring in UC remains unknown. Most studies use feces to represent the microflora distribution; however, here we analyzed the bacterial diversity in colonic mucus from UC patients receiving colectomy surgery and control patients. The diversity of microflora was investigated using a combination of terminal restriction fragment length polymorphism (T-RFLP) and clone library analyses of the 16S rRNA gene sequences. In the T-RFLP analysis, the number of terminal restriction fragments (T-RFs) decreased significantly in UC patients when compared to control samples. Also in the clone library analysis, the number of operational taxonomic units (OTU) and the Shannon diversity index were reduced significantly in UC patients. These molecular analyses reveal an overall dysbiosis in UC patients. No specific pathogen was found, and a strong negative correlation in relative abundance of bacterial populations was observed between the phyla Bacteroidetes and Firmicutes in the UC patients. This is the first report showing a significant correlation between these two phyla, which may be important characteristics in the pathogenesis of UC.
Soybean and fish oil mixture increases IL-10, protects against DNA damage and decreases colonic inflammation in rats with dextran sulfate sodium (DSS) colitis
Karina V Barros, Roberta AN Xavier, Gilclay G Abreu, Carlos AR Martinez, Marcelo L Ribeiro, Alessandra Gambero, Patrícia O Carvalho, Claudia MO Nascimento, Vera LF Silveira
Lipids in Health and Disease , 2010, DOI: 10.1186/1476-511x-9-68
Abstract: Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) characterized by recurrent episodes of colonic inflammation and tissue regeneration[1]. Although the pathogenesis of UC has not been entirely elucidated, the chronic relapsing inflammation has a multifactorial etiology. UC can be caused by an exaggerated immune response to the intestinal flora in the context of genetic predisposition [2,3] that can be attributed, at least in part, to an imbalance between effector T cells (Teff) and regulatory T cells (Treg)[4].In IBD, there is increased synthesis and release of pro-inflammatory mediators, such as eicosanoids, platelet activating factor, reactive oxygen species (ROS), nitrogen metabolites, chemokines and mainly cytokines [5] that have been associated with disease severity, activity and remission [2].Active episodes of UC are characterized by mucosal injury, increased vascular permeability, infiltration of neutrophilic polymorphonuclear, leukocytes, disruption of extracellular matrix and epithelial cell damage where the synthesis and release of ROS, triggered mainly by neutrophils, can mediate cell and tissues injury [6].Patients with IBD are at increased risk of developing colorectal cancer, and the inflammation has been associated with neoplastic changes through production of pro-inflammatory cytokines and ROS[7]. Both mediators activate nuclear transcription factor-kB (NF-kB), inducible nitric oxide synthesis, and cyclooxygenase-2-related signaling pathways, which may retard or suppress apoptosis in intestinal epithelial cells and modulate angiogenesis [8]. ROS, the cellular consequences of oxidative stress, may cause DNA oxidation, resulting in damage to all four bases and the deoxy-ribose-molecule [9,10]. Chronic inflammation in the colonic mucosa caused by increased and continuous exposure of ROS promotes oxidative DNA damage of the epithelial cells, triggering the appearance of genetic mutations and initiating colorectal carcinogenesis [10,11].Distu
Dietary Iron Enhances Colonic Inflammation and IL-6/IL-11-Stat3 Signaling Promoting Colonic Tumor Development in Mice  [PDF]
Anita C. G. Chua, Borut R. S. Klopcic, Desiree S. Ho, S. Kristine Fu, Cynthia H. Forrest, Kevin D. Croft, John K. Olynyk, Ian C. Lawrance, Debbie Trinder
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0078850
Abstract: Chronic intestinal inflammation and high dietary iron are associated with colorectal cancer development. The role of Stat3 activation in iron-induced colonic inflammation and tumorigenesis was investigated in a mouse model of inflammation-associated colorectal cancer. Mice, fed either an iron-supplemented or control diet, were treated with azoxymethane and dextran sodium sulfate (DSS). Intestinal inflammation and tumor development were assessed by endoscopy and histology, gene expression by real-time PCR, Stat3 phosphorylation by immunoblot, cytokines by ELISA and apoptosis by TUNEL assay. Colonic inflammation was more severe in mice fed an iron-supplemented compared with a control diet one week post-DSS treatment, with enhanced colonic IL-6 and IL-11 release and Stat3 phosphorylation. Both IL-6 and ferritin, the iron storage protein, co-localized with macrophages suggesting iron may act directly on IL-6 producing-macrophages. Iron increased DSS-induced colonic epithelial cell proliferation and apoptosis consistent with enhanced mucosal damage. DSS-treated mice developed anemia that was not alleviated by dietary iron supplementation. Six weeks post-DSS treatment, iron-supplemented mice developed more and larger colonic tumors compared with control mice. Intratumoral IL-6 and IL-11 expression increased in DSS-treated mice and IL-6, and possibly IL-11, were enhanced by dietary iron. Gene expression of iron importers, divalent metal transporter 1 and transferrin receptor 1, increased and iron exporter, ferroportin, decreased in colonic tumors suggesting increased iron uptake. Dietary iron and colonic inflammation synergistically activated colonic IL-6/IL-11-Stat3 signaling promoting tumorigenesis. Oral iron therapy may be detrimental in inflammatory bowel disease since it may exacerbate colonic inflammation and increase colorectal cancer risk.
Altering Mucus Rheology to “Solidify” Human Mucus at the Nanoscale  [PDF]
Samuel K. Lai, Ying-Ying Wang, Richard Cone, Denis Wirtz, Justin Hanes
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0004294
Abstract: The ability of mucus to function as a protective barrier at mucosal surfaces rests on its viscous and elastic properties, which are not well understood at length scales relevant to pathogens and ultrafine environmental particles. Here we report that fresh, undiluted human cervicovaginal mucus (CVM) transitions from an impermeable elastic barrier to non-adhesive objects sized 1 μm and larger to a highly permeable viscoelastic liquid to non-adhesive objects smaller than 500 nm in diameter. Addition of a nonionic detergent, present in vaginal gels, lubricants and condoms, caused CVM to behave as an impermeable elastic barrier to 200 and 500 nm particles, suggesting that the dissociation of hydrophobically-bundled mucin fibers created a finer elastic mucin mesh. Surprisingly, the macroscopic viscoelasticity, which is critical to proper mucus function, was unchanged. These findings provide important insight into the nanoscale structural and barrier properties of mucus, and how the penetration of foreign particles across mucus might be inhibited.
Lactobacillus Adhesion to Mucus  [PDF]
Maxwell L. Van Tassell,Michael J. Miller
Nutrients , 2011, DOI: 10.3390/nu3050613
Abstract: Mucus provides protective functions in the gastrointestinal tract and plays an important role in the adhesion of microorganisms to host surfaces. Mucin glycoproteins polymerize, forming a framework to which certain microbial populations can adhere, including probiotic Lactobacillus species. Numerous mechanisms for adhesion to mucus have been discovered in lactobacilli, including partially characterized mucus binding proteins. These mechanisms vary in importance with the in vitro models studied, which could significantly affect the perceived probiotic potential of the organisms. Understanding the nature of mucus-microbe interactions could be the key to elucidating the mechanisms of probiotic adhesion within the host.
Dietary Selenium Deficiency Exacerbates DSS-Induced Epithelial Injury and AOM/DSS-Induced Tumorigenesis  [PDF]
Caitlyn W. Barrett, Kshipra Singh, Amy K. Motley, Mary K. Lintel, Elena Matafonova, Amber M. Bradley, Wei Ning, Shenika V. Poindexter, Bobak Parang, Vishruth K. Reddy, Rupesh Chaturvedi, Barbara M. Fingleton, Mary K. Washington, Keith T. Wilson, Sean S. Davies, Kristina E. Hill, Raymond F. Burk, Christopher S. Williams
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0067845
Abstract: Selenium (Se) is an essential micronutrient that exerts its functions via selenoproteins. Little is known about the role of Se in inflammatory bowel disease (IBD). Epidemiological studies have inversely correlated nutritional Se status with IBD severity and colon cancer risk. Moreover, molecular studies have revealed that Se deficiency activates WNT signaling, a pathway essential to intestinal stem cell programs and pivotal to injury recovery processes in IBD that is also activated in inflammatory neoplastic transformation. In order to better understand the role of Se in epithelial injury and tumorigenesis resulting from inflammatory stimuli, we examined colonic phenotypes in Se-deficient or -sufficient mice in response to dextran sodium sulfate (DSS)-induced colitis, and azoxymethane (AOM) followed by cyclical administration of DSS, respectively. In response to DSS alone, Se-deficient mice demonstrated increased morbidity, weight loss, stool scores, and colonic injury with a concomitant increase in DNA damage and increases in inflammation-related cytokines. As there was an increase in DNA damage as well as expression of several EGF and TGF-β pathway genes in response to inflammatory injury, we sought to determine if tumorigenesis was altered in the setting of inflammatory carcinogenesis. Se-deficient mice subjected to AOM/DSS treatment to model colitis-associated cancer (CAC) had increased tumor number, though not size, as well as increased incidence of high grade dysplasia. This increase in tumor initiation was likely due to a general increase in colonic DNA damage, as increased 8-OHdG staining was seen in Se-deficient tumors and adjacent, non-tumor mucosa. Taken together, our results indicate that Se deficiency worsens experimental colitis and promotes tumor development and progression in inflammatory carcinogenesis.
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